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- Title
The PDGFRβ/ERK1/2 pathway regulates CDCP1 expression in triple-negative breast cancer.
- Authors
Forte, Luca; Turdo, Federica; Ghirelli, Cristina; Aiello, Piera; Casalini, Patrizia; Iorio, Marilena Valeria; D'Ippolito, Elvira; Gasparini, Patrizia; Agresti, Roberto; Belmonte, Beatrice; Sozzi, Gabriella; Sfondrini, Lucia; Tagliabue, Elda; Campiglio, Manuela; Bianchi, Francesca
- Abstract
<bold>Background: </bold>CDCP1, a transmembrane protein with tumor pro-metastatic activity, was recently identified as a prognostic marker in TNBC, the most aggressive breast cancer subtype still lacking an effective molecular targeted therapy. The mechanisms driving CDCP1 over-expression are not fully understood, although several stimuli derived from tumor microenvironment, such as factors present in Wound Healing Fluids (WHFs), reportedly increase CDCP1 levels.<bold>Methods: </bold>The expression of CDCP1, PDGFRβ and ERK1/2cell was tested by Western blot after stimulation of MDA-MB-231 cells with PDGF-BB and, similarly, in presence or not of ERK1/2 inhibitor in a panel of TNBC cell lines. Knock-down of PDGFRβ was established in MDA-MB-231 cells to detect CDCP1 upon WHF treatment. Immunohistochemical staining was used to detect the expression of CDCP1 and PDGFRβ in TNBC clinical samples.<bold>Results: </bold>We discovered that PDGF-BB-mediated activation of PDGFRβ increases CDCP1 protein expression through the downstream activation of ERK1/2. Inhibition of ERK1/2 activity reduced per se CDCP1 expression, evidence strengthening its role in CDCP1 expression regulation. Knock-down of PDGFRβ in TNBC cells impaired CDCP1 increase induced by WHF treatment, highlighting the role if this receptor as a central player of the WHF-mediated CDCP1 induction. A significant association between CDCP1 and PDGFRβ immunohistochemical staining was observed in TNBC specimens, independently of CDCP1 gene gain, thus corroborating the relevance of the PDGF-BB/PDGFRβ axis in the modulation of CDCP1 expression.<bold>Conclusion: </bold>We have identified PDGF-BB/PDGFRβ-mediated pathway as a novel player in the regulation of CDCP1 in TNCBs through ERK1/2 activation. Our results provide the basis for the potential use of PDGFRβ and ERK1/2 inhibitors in targeting the aggressive features of CDCP1-positive TNBCs.
- Subjects
TRIPLE-negative breast cancer; MEMBRANE proteins; PLATELET-derived growth factor; PROTEIN expression; IMMUNOHISTOCHEMISTRY
- Publication
BMC Cancer, 2018, Vol 18, Issue 1, p1
- ISSN
1471-2407
- Publication type
journal article
- DOI
10.1186/s12885-018-4500-9